Colorectal cancer represents one of the leading causes of cancer-related mortality in the U.S. Hyperproliferation of colonic epithelium is now recognized as a risk factor for colorectal cancer. Factors that increase proliferation of colonic epithelium are believed to play a role in colon carcinogenesis. We now know that fully processed amidated gastrins (G17) and unprocessed non-amidated gastrins (gly-gastrin and progastrin, PG) are mitogenic for normal and cancerous intestinal cells. Our recent studies with mutant mice that over-express either PG or G17 or lack the functional gastrin gene (GAS-KO), suggest the novel possibility that PG is a co-carcinogen, while amidated gastrins inhibit rather than stimulate colon carcinogenesis. Differential effects of amidated (G17) vs non-amidated (PG) gastrins on colon carcinogenesis is a novel finding that will be further investigated in this application. The major hypothesis of this proposal is that PG increases the risk while G17 decreases the risk of colon carcinogenesis in response to chemical carcinogens. In Aim 1 we will confirm if PG is equally co-carcinogenic at physiological concentrations using more appropriate mutant mouse models. Possible dose-dependent effects of PG on colon carcinogenesis will be examined by treating GAS-KO mice with increasing concentrations of PG. In Aim 2 we will investigate the novel possibility that G17 reduces the risk of colon carcinogenesis, by either using mutant mouse models that over-express G17, treating GAS-KO mice and their wild type (WT) littermates with increasing concentrations of G17, or reducing endogenous levels of gastrins in WT mice. In Aim 3 we will investigate a role, if any, of gastrin receptor subtypes in mediating differential effects of PG vs G17. We recently reported a novel finding that PG may function as an anti-apoptotic factor for colon cancer cells and intestinal epithelial cells. In Aim 4, we will examine relative effects of PG vs G17 on apoptotic potential of colonic mucosal cells, that may help to explain differential effects between the two peptides. Results of the studies in the four Aims will allow us to confirm our novel hypotheses, and provide important mechanistic clues that will form the basis of studies in future funding periods. These results are expected to impact diagnosis, prognosis and clinical management of patients with colon cancer.